Process for the production of 12beta-methyl-delta5, 17(20)-pregnadiene-11 oxygenated-3-ketal derivatives



United States Patent 3,087,925 PROCESS FOR THE PRODUCTION OF H S-METH- YL-A -PREGNADIENE-ll OXYGENATED-3- KETAL DERIVATIVES, Burton G. Christensen, Rahway; Ralph F. Hirschmann, Scotch Plains, and-101m M. Chemerda, Metuchen, N.J.,

assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Aug.; 7; 1 9 58, Ser. No. 753,641 2 Claims. (Cl. 260-23955) This invention is concerned generally with novel steroid compounds and with processes of preparing the same; more particularly, it relates to llfi-alkyl-ll-oxygenatd steroids of the pregnane series unsaturated in ring It relates also to novel processes for producing IZB-aIkyl steroids.

The new products of our invention may be represented by the structural formula- OHrOR {Wit wherein R may be the same or different alkyl groups.

The alkyl 12a-alkyl 3-ethylenedioxy 11B liydrorry-5,l7 (20)-pregnadien 21-oate used as a starting material for the present invention is prepared by hydrolyzing' 3d-acyloxy-12u-halo-11,20-pregnanedione to form 12a-halo-3ahydroxy-l 1,20-pregnanedione.

The latter compound is then reacted with an oxidizing agent and the 12a-ha1o-3;11,20-pregnanetrione, thus formed, is reacted with ethylene glycol in the presence of an acid catalyst to obtain 12bz-halo-3,20-bis-[ethylenedioxy]-1l-pregnanone. This latter compound is then reacted with lithium borohydride to form 12a-halo-3,20-bis- [ethylenedioxy]-1 l fl-hydroxypregnane and the latter compound is reacted with base to yiefld 11fl,12fl-epoxy-3,20- bis-[ethylenedioxy]-pregnane. This compound may be caused to react with dialkylmagnesium and hydrolysis of the 120: alkyl-3,ZO-liis-iethylenediuy]-1lfi-hydroxypregnane thus obtained with acid such as dilute sulfuric acid in methyl alcohol results in the formation of 12u-alky1- 11B-hydroxy-3,ZO-pregnanediBn which is reacted with a halogenating agent to form 12a-alkyl 4-halo-1LB-hydroxy- 3,20-pregn'anedione.

Dehydrohalogenation of latter compound with a reagent such as collidine or lithium chloride in dimethyl: formamide results in the formation of l2 x alkyll lfi hydresygtpregnene azoaiofie and the 2l-glyoxylate ester is prepared by reacting lgd allgyl-l lp-hydroxy-4- prefgnene 3,20 dio'ne with a dialkyl oxalatstdform alkyl lZialkylf 11 3,21 dihydroiy 4-pregnne-3,ZQ-dione 2 1-glyoxylate. Reacting the alkyl Hat-alkyl-I l18,2ldihydroxy 4;p1fegnene 3',20'-dione' ZI 'glyoXyI'ate with a halogen results in the formation of alkyl 12a-a1ky1-2L21-dihalo-1IB-hydroXY- F pregnene-3,20-dione21 glyoXylate. The latter compound, namely, alkyl 12a-alkyl-21,2 1-dihalo-11,6-hydroxy-4-pregnene-3,20-dione 21-glvoxyla'te, is reacted with sodium methoxide and then with a diazoalkane compound to form caused to react with an oxidizing agent such as chromimum trioxide in pyridine to form alkyl 12a-alkyl-3 -ethylenedi QM-,5,17(2Q1-pregnadien-11 one 21-oates which have the following structural formula wherein R is alkyl and R is hydrogen or alkyl.

Whereas the 12a-alky1 group is stable to base when the substituent at C-11 is an hydroxy group, the 12 alkyl group is isomerized to the HE-position by base when there is a keto group at position 11 Consequently, reap; t ion of the above a1 kyl-1 2 o;-a ll yl-3-ethylenedioxy-5,17 (20) -p r egi adien:-1I-one 21-oate with potassium hydroxide and isopropyl alcohol resulted after isolation, and reesterificationj at 0-21 with diazoalkane in the formation of 1Zfl-alkylfi-ethy1enedioxy-5,'17 20) -pregnadie1i-1'1'-'one Zl-oate which may be represented as follows; wherein the solid line denotes the 12fl-p'osition, and, whereih R is" alkyl and R is the same or different alkyl groups.

The alkyl 1'2fi-alkyl-3-ethylenedibi y-S;17(ZOfipregna dien ll one 2'l"-oate can be reduced With lithiuinfaluminu-m hydride to form IZfi-alkyl-3-ethylenedioxy-111221 dihydroXy-S,l7(20)-pregnadiene which has the following formula GHzOH wherein R is alkyl.

Reaction of the 12p-alkyl-3-ethylenedioxy-1lfi-hydroxy- 5,17(20)-pregnadiene with an acid under mild conditions such as dilute acid in a methanolic medium results in the removal of the ethylenedioxy group in the 3-position and there is obtained 12 3-alkyl-115,21-dihydroxy-4,17(20)- pregnadien-S-one which may be represented graphically as follows:

wherein R is alkyl.

Reaction of the above with an acyl anhydride results in the formation of the 21-acylate, namely, 12/3-alkyl-11,8, 21-dihydroxy-4,l7(20)-pregnadien-3-one 2l-acylate. The latter compound is then reacted with osmium tetroxide and hydrogen peroxide to form 12fl-alkyl-11,B,17a,21-trihydroxy-4-pregnene-3,20-dione 2l-acylate which may be represented as follows:

OHaOH Ho 5 tQU wherein R is as above.

This latter compound, namely, 12fl-alkyl-1lfl,l7a,2ltrihydroxy-4-pregnene-3,ZO-dione 2l-acylate may also be named 12,3-alkyl-hydrocortisone acylate and possesses marked and effective anti-inflammatory activity.

The above l2p-alkyl-11,3,17a,21-trihydroxy-4-pregnene- 3,20-dione 2l-acylate can be dehydrated with methanesulfonyl chloride in pyridine or dimethylformamide to form 12fl-alkyl-17a,21-dihydroxy-4,9( l 1 -pregnadiene-3 -dione 21-acy1ate which may be represented by the following structural formulawherein R is alkyl and R is hydrogen or acyl.

. Treatment of the l2fl-alkyl-l7a,21-dihydroxy-4,9 1 1 pregnadiene-3,20-dione 21-acylate with N-halosuccinimide 4 in the presence of an acid catalyst results in the formation of 12B-alkyl-9a-halol 1, 17a,2l-trihydroxy-4-pregnene-3, 20-dione 21-acylate which has the following structural formula:

wherein R is alkyl, R is hydrogen or acyl and X is bromo and chloro.

The 12,8-alkyl-9a-halo-1 1,17a,2l-trihydroxy-4-pregnene- 3,20-dione Ill-acylate is then reacted with sodium alkoxide to form 12,8-alkyl-9fi,1lfi-epoxy-l7a,21-dihydroxy-4-pregnene-3,20-dione and reaction of the latter compound with an acyl anhydride in the presence of pyridine results in the formation of 12B-alkyl-9;3,11;8-epoxy-17a,2l-dihydroxy-4-pregnene-3,20-dione 21-acylate which may be represented as follows:

onion R =o I OH wherein R is alkyl and R is hydrogen or acyl.

Reaction of the 12fi-alkyl-9fi,llp-epoxy-17ht,2l-dihydroXy-4-pregr1ene-3,20-dione 21-acylate with a hydrogen halide results in the formation of l2fl-alkyl-9a-halo-llfl, 17a,2l-trihydroXy-4-pregnene-3,20-dione 21-acylate which has the following structural formula:

OHIO R I "OH HO i r:

wherein R is alkylyR" ishyd'rogen or acyl andY is. hydrogen" or halogen.

Alternatively, the 1,4*-pregnadiene compounds described above'can be preparedtrom' thecori'esponding 4'-pregnene- 3-ones microbially' by means of Bacillus sphaericws;

Compoundsdiscussed= hereinbefore and having. the following formula:

salon 0:

wherein- R is alkyLR is hydrogen or acyl,- Y is hydrogen or halogen and the broken line between positions 1 and 2 indicates that a double bond may be present in-this position can be oxidized with chromium trioxide in the presence of pyridine to convert the 11 ,B-hydroxy group to a: keto group and the oxidation product can be represented by the following formula:

gen or halogen.

Compounds of the following structure:

wherein R is alky1,.Y is hydrogenor halogen, Z is hydroxy or'ke'to and the" brokenlme between carbon atoms 1 and 2 indicate that a doubl'eborid-m'ay be present can bereactedwith' acid to formtlie corresponding.21-alcohol;

CHaOH In addition; it has been found that where'a 9'a fluoro 21- acylate or the 9a-hydrogen ll acyl-ate is hydrolyzed to tlie alcohol, sodium methoxide may be employed In all of the previously described reactions R has been designated as alkyl, andis'iritended to include the lower alkyl group'ssueh asmethyl; ethyl and pr'opylz R has been indicated as hydrogen or acyl and the acyl groups that may be employed in these reactions include lower hydrocarbon carbonyl esters such as benzoate, lower a'lkano'ates such as acetate, andpropionate, Y is hydrogen or halogen and halogen is intended-to include bromo';

chlo ro iodo and fluoro. It will be evident to those skilled in the art that other groups may be substituted for those recited here and these definitions are intended only as some indication of the operable class of compounds intended. I

The following experimental part illustrates in detail some of the compounds which constitute this invention and methods for their production. However, this invention is not to be construed as limited thereby in spirit or in scope since it will be apparent to those skilled in the art that many modifications in materials and methods may be made without departing from the invention.

EXAMPLE 1 Preparation of Methyl 3-Ethyle'nedi0Xy-12tit-Methyl 5,17(20) -Pregnadien-11-0ne-21-Oate 1*.25 grams of chromium trioxide was added in portions to 12.5 ml. of dry pyridine in the cold. To the mixture was added 1.25 g. of methyl 3-ethylenedioxy- 11fl-hydroxy-12a-methyl-5,17(20) pregnadien 21' o'ate (prepared as described herein below) in 2.5 ml. of pyridine. The mixture stood at room temperature for about 16 hours and was then distributed between other and water, The organic layer was washed with dilute hydrochloric acid, with Water, with sodium bicarbonate and ffi'riall-y' With saturated salt solution. Removal of the solvent alforded after crystallization the desired methyl- 3'-e'thylendioxy'-Du-methyl 5,17(20) pregnadien 11- one- 2 l-oate.

The 3-ethylenedioxy-21-hydroxy-12a-methyl-5, 17 (2O pregriadien 21 -oate used as a starting. material in this example is prepared; starting with the known 3oc-acetoxyl 2a=bromo-l1 ,20 pregnanedione in accordance with the following procedure! A mixture of 50 g. of 3'u-acetoxy- 12oc-bromo-ILZO-pregnanedione, 518' liters of methanol and 51.8 ml. of concentrated hydrochloric acid was stirred for 20 hours at about 20 C. The reaction was quenched by adding a solution of 27.6 g of sodium bicarbonate in 690 ml.- of water with stirring. The product 12a-bromo-3e-hydroxy-l1,20-pregnanedione, was isolatedby removing the methanol invacuo, adding 1' liter ofWaterandfilteringjMP. 157-159" C.

To" a solution of 39.78 g. of 12a-bromo-3a-hydr'oxy- 1'1,20- pi egnanedione in 971 ml. of methanol was added 9.71 ml; of dry pyridine. The flaskwas covered with a" black clothand continuously stirred at about 20 C. solution of 7517 g; of N-bromoacetamide in 971 ml. of methanol vv'a'sadded'and the mixture was stirred for 20 hours; Twenty millilitersof allyl alcohol were added; followed by 3 liters of Water. The product, 12uc-brorno- 3jl li20 preghane trione which crystallized on standing was filtered ofl; MiP. 189-191 C.

A solution-of 39.98 g. of 12d-brorn'o-3',l1,20 pregnanetrione; 1,075 g; of p tbluen'esulfonic acid monohydrate; 2426 ml. of freshly distilledetliylene'glycol and 924 ml. of benzene,-thathad 'been previously dried over sodium, was slowly distilled through a Vi'greux column for 5 hours, keeping the volume constant'by adding dry benzene. The reaction was extracted twice with 5% sodium bicarbonate'soliition and washed once With water. It Wasd'riedover anhydrous sodium sulfate for about 16 hours, filte'r'e'd and the filtrate concentrated in vacuo. The: product, l2-a-bromo-3i20 bis-[ethylenedioxy]-11- preg manone vv' as crystallized 'from" acetone-methanol; M.P. 173-1-7-5"C.'-

dioxy]-11-pregnanone in 300 ml. of tetrahydrofuran was cooled te"0" C. The systemwas purged withnitrogen.

ml. oftatrahydrbfiiian was added over a'" period of 45 minutes witlistir'r'in'g. The solution was allowedto come' was added. The aqueous layer was extracted three times with chloroform and the combined organic extracts were washed with sodium bicarbonate and water and dried over anhydrous sodium sulfate overnight. It was filtered and the filtrate concentrated in vacuo; 12u-bromo- 3,20-bis-[ethylenedioxy]-llB-hydroxy-pregnane was recovered.

To a solution of 19.5 g. of potassium hydroxide in 325 ml. of isopropanol, 6.51 g. of 12a-bromo-3,20-bis [ethylenedioxy]-1lp-hydroxypregnane were added and the system was purged with nitrogen. The reaction mixture was stirred for 1.5 hours at 55 C. and during this time a copious precipitate of potassium bromide formed. The reaction mixture was poured into the water, and was back-extracted three times with ether. The ether was back-extracted with water and dried over anhydrous sodium sulfate overnight. Filtered and concentrated in vacuo to a small volume; the resultant needles of 115, l2/3-epoxy-dione-3,20-bis- [ethylenedioxy] -pregnane were filtered oif.

To 1.00 g. of 11B,12fi-epoxy-3,20-bis-[ethylenedioxy]- pregnane was added 20.0 ml. of a dioxane solution of dimethylmagnesium (19.07 milliequivalents). All apparatus had been previously flame-dried under a stream of dry nitrogen. The solution was refluxed for sixteen hours under a nitrogen atmosphere. At the end of this time, a saturated solution of ammonium chloride was added until the gaseous evolution ceased upon addition of further amounts of the solution. The layers were separated and the aqueous layer was extracted three times with chloroform. The combined organic layers were washed with water, dried over anhydrous sodium sulfate overnight, filtered and concentrated to an oil in vacuo on the hot water bath. The oil thus obtained contained 3,20-bis- [ethylenedioxy] -1 1,8-hydroxy-l2a-methylpregnane.

To the oil containing 3,20-bis-[ethylenedioxy]-l1,8-hydroxy-l2a-methylpregnane was added 270 ml. of meth-' anol and 10.8 ml. of 8.5% sulfuric acid. The solution was refluxed for 1% hours under a nitrogen atmosphere and then cooled. Solid sodium bicarbonate was added until the solution was neutral. The solution was filtered and the methanol was removed in vacuo on the hot-water bath. Water was added and the aqueous layer was extracted three times with chloroform. The combined extracts were washed with water and dried over anhydrous sodium sulfate for 1% hours. They were filtered, concentrated to dryness in vacuo on the hot-water bath and crystallized from methanol-ether to yield 11fi-hydroxy 12a-methyl-3,20-pregnanedione.

One hundred grams of 1lfi-hydroxy-12a-methyl-3,20- pregn-anedione in 2 liters of chloroform and 225 ml. of acetic acid is cooled to 50 C. and brominated with 40.6 g. of bromine in 227 ml. of acetic acid. After one hour, 40.25 g. of sodium acetate in 300 ml. of water was added, the reaction mixture concentrated to 600 ml. and 4-bromo-11B-hydroxy-12a-methyl-3,20-pregnanedione was collected by filtration after the addition of 1 liter of water.

To a solution of 170 mg. of 4-bromo-11B-hydroxy-12umethyl-3,20-pregnanedione in 2.0 ml. of dimethylform amide was added 51 mg. of anhydrous lithium chloride. The mixture was heated to 100 C. for 2 hours under a nitrogen atmosphere. One milliliter of water was added dropwise with stirring before cooling to 0 C. The 11 8- hydroxy-l2a-methyl-4-pregnene 3,20 dione was filtered 01f and dried; wt. 115 mg.

40 grams of 1lp-hydroxy-12a-methyl-4-pregnene-3,20- dione was dissolved in 200 ml. of benzene and 14.6 g. of diethyl oxalate. After the addition of 5.6 g. of sodium methoxide, the mixture was stirred for two hours to form ethyl 1 1,3,2 l-dihydroxyl ZOL-IHGthYl-4-[P1'CgI1CI1C-3,20-dl0116 2l-glyoxylate.

The ethyl 11fi,2l-dihydroxy 12a methyl -'4-pregnene- 3,20-dione 2-glyoxylate was reacted with 32 g. of bromine 8 in ml. of benzene at 10 C. and kept at 10 C. for one hour to form ethyl 21,21-dibromo-1lfi-hydroxy-l2a-methyl-4-pregnene-3,20-dione 2l-glyoxylate.

The mixture containing ethyl 21,21-dibromo-11fl-hydnoxy-l2a-methyl-4-pregnene 3,20 dione 21-glyoxylate was added to 500 ml. of 10% of methanolic sodium methoxide solution and maintained at room temperature for about 16 hours. After concentration of the reaction mixture to dryness, the residue was refluxed with 500 ml. of 5 N methanolic sodium hydroxide, the reaction mixture was diluted with water and concentrated to flush out methanol. Acidification yielded 1l/3-hydroxy-12a-methyl-3- oxo-4,17(20)-pregnadien-21-oic acid which was collected on filtration. After drying at room temperature, the 11/3- hydroxy-l2a-methyl-3-oxo-4,17(20)- pregnadien 21 oic acid was treated with excess ethereal diazomethane. After esterification was complete, the ethereal solution was chromatographed over acid-washed alumina to give 1lfi-hyd-roxy-12a-methyl-3-oxo-4,17(20)- pregnadien 21- oate.

10 grams of methyl 1IB-hydroxy-l2a-methyl-3-oxo-4, 17(20)-pregnadien 2l-oate was dissolved in 100 g. of ethylene glycol and 500 cc. of benzene, 0.25 g. of p-toluenesulfonic acid was added and the reaction mixture refluxed for 5 hours with a benzene-water separator. At the end of this period, 10 g. of sodium bicarbonate was added and the mixture poured into 1 liter of water. The resultant 3-ethylenedioxy-l lfl-hydroxy-l2a methyl-5,l7(20)-pregnadien 21-oate was extracted into benzene, the benzene solution dried and concentrated to dryness.

EXAMPLE 2 Preparation of 3-Ethylenedi0xy-12B-Methyl-5,17(20)- Pregnadien-Il-One 21 -Oate The 3-ethylenedioxy-1 1/3-hydroxy-12a-methyl-5, 17 20) pregnadien-l l-one 21-oate was refluxed for three hours in a solution of potassium hydroxide in isopropyl alcohol. Water was added and the alcohol was removed by distillation. The pH was made acid to Congo red and the acid extracted into ethyl acetate. After removal of the solvent the residue was dissolved in methanol and esterified with diazomethane. The resulting methyl 3-ethylenedioxy- 12fl-methyl-5,17(20)-pregnadien-1l-one 21-oate was crystallized and isolated by filtration.

EXAMPLE 3 Preparation of 3-Ethylenedioxy-11;3,21-Dihydr0xy-12}3- M ethyl-5 ,1 7(20) -Pregnadiene The methyl 3-ethylenedioxy-12,8-methyl-5,17(20)-pregnadien-ll-one 21-oate was dissolved in 2 M lithium aluminum hydride in ether solution and kept at room temperature for about 16 hours, to form 3-ethylenedioxy-ll 3, 2 l-dihydroxy-12/3-methyl-5, 17 (20) -pregnadiene. The mixture was diluted with water and 2 N hydrochloric acid. The ether was removed by distillation and 3-ethylenedioxy-l113,2l-dihydroxy-lZfl-methyl 5,17(20) pregnadiene was collected by filtration.

EXAMPLE 4 Preparation 0 f 115,21-Dihydr0xy-12,B-Methyl-4,17(20) Pregnadien-S-One A solution of 2 g. of 3-ethylenedioxy-1lfi,2l-dihydroxy- 12p-methyl-5,17(20)-pregnadiene in ml. of acetone was boiled briefly on the steam bath with 8 ml. of 1 N sulfuric acid. After neutralization 1113,21-dihydroxy- 12fi-methyl-4,17(20)-pregnadiene-3-one was obtained.

EXAMPLE 5 Preparation of 11 8,21 -D ihydr0xy-12fl-Methyl-4J 7 (20) Pregnadiene To the 11,3,21-dihydroxy-l2fl-methyl-4,17(20)-pregnadien-3-one was added pyridine and acetic anhydride and 113,21-dihydroxy-12;3-methyl-4,17(20)-pregnadien-3 one 21-acetate was recovered.

9. EXAMPLE 6 Preparation of 1113,] 70;,21-Trihydroxy-12fl-Methyl-4- Pregnene-3,20-Dine 21 -Acetate 6.85 g. of the 11,8,21-dihydroxy-12 3-methyl-4,17(20-)- pregnadien-3-one 2l-acetate was dissolved in 200 ml. of t-butyl alcohol and reacted with 3 ml.- of pyridine, 191 mg. of osmium tetroxide and 1.3 g. of hydrogen peroxide. After 4 days, the reaction mixture was stirred with 4.2 g. of sodium sulfite in 190 ml. of water, tbutyl alcohol was removed in vacuo and the product extracted with methylene chloride. Chromatography ove'r diatomaceous earth yielded pure 11B,17a,21-trihydroxy-12p-methyl 4 pregnene-3,20-dione 2l-acetate.

EXAMPLE 7 Preparation of J 7a,2I-Dihydr0xy-J2B-Methyl-4,9 (11 Pregnadiene-3,20-Di0ne 21 -Acetate An 11.07 g. aliquot of l1,8,l7u,2l-trihydroxy-lZfi-methyl-4-pregnene-3,20-dione Zl-acetate was dissolved in a mixture of 65 cc. of dimethylformamide and 11 cc. of pyridine in a dry Z-liter three-necked flask, fitted with a stirrer and reflux condenser. 5.55 cc. of methane-sulfonyl chloride was added at room temperature. The reaction mixture was held at 80-85 C. for one hour. The solution was chilled in an ice bath and treated successively with 110 cc. of methanol, 480 cc. of aqueous sodium bicarbonate and finally with 360 cc. of water while stirring in an ice bath. The product 17oc,2 I -dihydrQXy-IZB-methyl-4,9(l1)-pregnadiene-3,20-dione 2l-acetate was then removed by filtration without difficulty, washed repeatedly with water and dried to constant weight in a Moisture Teller at 50 C. (30 minutes).

EXAMPLE 8 Preparation of 9u-Br0m0-115J 7u,21-Trihydr0xy-12fl- M ethyl-4-Pregn'ene-3 ,ZO-Dione 21 -Acetate To a suspension of a 9.03 g. aliquot of the above 1711,21 dihydroxy 123- methyl 4,9( l'l) pregnadiene- 3,20-dione 21-acetate in 114 cc. of acetone was added at 0 C. with stirring 5.93 g. of N-br'omosuccinimide (96%- by titration) and then 20.4 cc. of a perchloric acid solution prepared by dissolving 0.548 cc. of- 70% perchloric acid in 33 cc. of water. The mixture was stirred .at 0 C. for 4% hours. The excess of N-bromosuccinimide was destroyed by the addition of allyl alcohol (40 drops) and 500 cc. of water was then added with a stirring over a 3-5 minute interval. The mixture was held at 0 C. for an additional hour. The 9a-bromo-1'1B,17a,2l-trihydroxy-l2fi-methyl-4-pregnene-3,20-dione 2l-acetat'e was removed by filtration, Washed repeatedly with water and dried in a desiccator over sulfuric acid.

EXAMPLE 9 Preparation of 913,115-Ep0xy-17a,21-Dihydroxy-12fl- M ethyl-4-Pregnene-3,20-D ions 21 -A cetate A 10.48 g. aliquot of 9a-bromo-llB,17a,2l-trihydroxyl2/3-methyl-4-pregnene-3,20-dione 2l-acetate was dissolved in 76.5 cc. of tetrahydrofuran (which had been briefly stored over potassium hydroxide) and 38* cc. of purified methanol. The mixture was treated with 25.8 cc. 0.91 N sodium methoxide in methanol in a nitrogen atmosphere at 24 C. for 5 minutes. The base was neutralized by the addition of an excess (1.58 cc.) of glacial acetic acid which resulted in a color change from red to dark yellow. The solvents were removed in vacuo at 4548 C. bath-temperature. The residue was flushed with chloroform and then with a petroleum ether. The residue was suspended in 48 cc. of pyridine and 24 cc. of acetic anhydride and heated under nitrogen at 65 C. for 1% hours. After removal of the reagents in vacuo (bath temperature up to 70 C. oil pump) the solid residue was flushed with petroleum ether. About 8.0 cc. of water was added and 913,1lfl-epoxy-17a,2l-dihydroxy- 10 1:2a mthyl-4-pregnene 3,20-dione ZI-acctate was filtered ofland washed thoroughly withwa'ter. The crude product was dissolved in 88 cc. of acetone, was treated with l g. of activated carbon and filtered. The activated carbon was washed free of the 95,11B-epoxy l7u,2l-dihydroxyl=2fl methyl-4-preg'nene-3,20-dione Zl -acetate. The clear, filtrate was concentrated on a steambath in a current of nitrogen and treated with-petroleum ether. Filtration and washing with acetone petroleum ether (1:10) gave the 9,3 1 1 6- epoxy 170:,21 dihydroxy 128 methyl 4- pregnene-3,20'-dione 21-acetate.

EXAMPLE 10' Preparationof 9a-Fuar'o-1I1 r17a,21 Trih droxy-12e- M ethyl-4-Pregnene iZO DiOne 21 -A c'eta'te' To a solution of 6.96- g. of anhydrous hydrogen fluoride in 13.24 g. of tetrahydrofuran and 5 ml. of chloroform chilled to about 60 C. was added asolut-ion of 4.018 g. of 9B,1 113 epoxy l7a,2l dihydroxy 12B methyl 4- pregnene-3,20-dione ZI-aceta'te in 25 ml. of chloroform likewise chilled at about --60 C. The hydrogen fluoride tetrahydrofu'ra'n reagent was immersed in an acetone- Dry Ice bath while the steroid was being added. An additional 5 ml. of chloroform was used to aid in the transfer of the epoxide'. The reaction mixture was removed f'rom the acetone-Dry Ice bath and subsequently maintained at ---30 C. for four hours and then added at a suitable rate to a well agitated mixture of an aqueous solution of potassium carbonate, chloroform and ice. The Weakly alkaline aqueous layer was separated and twice back extracted with chloroform. The combined organic layers were washed with water. After removal of the solvent in vacuo the-residue was heated with 5 ml'. of pyridine and 3 ml. of acetic anhydride at 65 C. under nitrogen for 75 minutes to convert any byproduct into a less polar diacyl derivative. The bulk of the solvents was removed in vacuo, and the residue was distributed between chloroform and dilute hydrochloric acid. The aqueous layer was back-extracted twice with chloroform. The combined organic layers were washed with dilute acid; with water, with a solution of bicarbonate and finally with water. The filtered solution was concentrated in vacuo to a small volume and' purified by passage through a column of neutral alumina (16 g'.). The eluates, amounting to ml. of chloroform,- were concentrated and the fluorohydrin was obtained by the addition of benzene. One recrystallization from acetonepetroleum ether afforded 9a-fluoro-llB,17a,2l-t1ihydroxy- 12fi-methyl-4-pregnene-3,20-dione ZI-acetate.

EXAMPLE 11 Preparation of 9a-Flaoro-1 '1 5,1 7a,21-Trihydr0xy-I2fl- M ethy l-4-Pregnene-3,20-Di0ne To a stirred solution of 100 mg. of 9a-fluor o-llfl,l7a, 21 trihydroxy 12B methyl 4 pregnene 3,20 dione 'Zl-acetate in 5 ml. of methanol under nitrogen at 25 C. was added 1.00 ml. of 025 M methanolic sodium methoxide. After 15 minutes 0.2 ml. of acetic acid in 1 ml. of water was added and the mixture concentrated nearly to dryness. The residue was taken up in ethyl acetate and the ethyl acetate solution was washed with water, dried over magnesium sulfate, and concentrated to dryness. Crystallization of the residue from ethyl acetate gave 90; fluoro l1B,l7a,2l trihydroxy 12,8-methyl 4- pregnene-3,20-dione.

EXAMPLE 12 Preparation of 9a-Chl0r0-1]B,1.7a,21-Trihydr0xy-12fl- M ethyl-4-Pregnene-3,20-Dione 21-Acetate To a solution of mg. of 9,8,1lfi-epoxy-17a,2l-dihydroxy 12B methyl 4 pregnene 3,20 :dione 21- acetate prepared as in Example 9 in 4" ml. of chloroform was added 5 ml. of concentrated hydrochloric acid; The two-phase mixture was stirred at.25 C. for 1 hour, addition of water and chloroform extraction gave a crude crystalline product which is partly deacetylated. Treatment with 1 ml. of pyridine and 0.5 ml. of acetic anhydride at 25 C. for 18 hours followed by concentration in vacuo and crystallization of the residue from acetoneether afforded pure 9a-chloro-115,17a-21-trihydroxy-12B- methyl-4-pregnene-3,2'0-dione 2l-aoetate.

EXAMPLE 13 Preparation of 9a-Chl0r0-1 113,1 70:,21 -Trihydrxy-1 218- M ethyl-4-Pregnene-3,20-Di0ne A solution of 250 mg. of 9a-chloro-11fi,17a,21-trihydroxy-12/3-methyl-4-pregnene-3,20-dione 21-acetate in 5 ml. of 0.25 N perchloric acid in methanol was stirred for about 18 hours at room temperature to produce 9ot-Chl010- 1lB,17a,21 trihydroxy 12p methyl 4 pregnene- 3,20-dione which is recovered by adding water to the reaction mixture and allowing the product to crystallize.

EXAMPLE 14 Preparation of 11 5,1 70:,21 -Trihydr0xy-1 ZB-Methy H ,4- Pregnadiene-3,20-Di0ne 21 -A cetate To 100 mg. of 11,8,17a,21trihydroxy-12B-methyl-4- pregnene-3,20-dione 21-acetate (prepared as in Example 6) in 5 ml. of t-butanol and 0.1 ml. of acetic acid was added 50 mg. of selenium dioxide. The mixture was refluxed under nitrogen for 18 hours, 50 mg. of selenium dioxide was added and the mixture refluxed for an additional 24 hours. The mixture was filtered and the filtrate taken to dryness. The residue was taken up in ethyl acetate and washed successively with aqueous sodium bicarbonate, ammonium sulfide, dilute ammonia water, Water, dilute hydrochloric acid and water and dried over magnesium sulfate. It was then treated with activated charcoal and concentrated to dryness. Crystallization of the residue from acetone-ether gave pure 11B,l7a,21-trihydroxy-12,8-methyl-1,4-pregnadiene-3,20-dione 21-acetate.

EXAMPLE 15 Preparation of 11,8,1 70:,21-Trihydr0xy-12u-Methyl-1,4- Pregnadiene-3,20-Dione llfl',l7oc,21 trihydroxy 12/3 methyl-1,4-pregnadiene- 3,20-dione 21-acetate can be reacted with methanolic sodium methoxide to produce the alcohol namely ll/3,17% 21 trihydroxy 12,8 methyl 1,4 pregnadiene 3,20- dione. This procedure is described in Example 11.

EXAMPLE 16 Alternatively, the 1,2-dehydrogenation of 11fl,17u,21- trihydroxy-12fl-methyl-4-pregnene-3,20-dione 21-acetate can be carried out microbiologically by means of Bacillus sphaericus to yield 11,8,Hall-trihydroxy-12fl-methyl-1,4- pregnadiene-3,20-dione which on acetylation with acetic anhydride-pyridine gives 11,6,17a,2l-trihydroxy-IZB-methyl-1,4-preguadiene-3,20-dione 21-acetate.

EXAMPLE 17 Preparation of 9oc-Flu0)'0-11 3,1 711,21 -Trihydroxy-I2}9- M ethyl-1 ,4-Pregnadiene-3,20-Dione 21 -A cetate In a similar manner, 100 mg. of 9ot-flllOI'O-1lfl,l7oc,21- .trihydroxy-12,6-methyl-4-pregnene-3,20-dione 21-acetate (prepared as described in Example 14) was treated selenium dioxide to produce the corresponding 9u-fiuoro- 11/3,17a,21 trihydroxy 1213 methyl 1,4 pregnadiene- 3,20-dione ZI-acetate.

EXAMPLE 18 Preparation of a 9a-Fla0r0-11BJ 7a,21-Trihydr0xy-1218- Methyl-1,4-Pregnadiene-3,20-Dione The 21-alcohol was prepared from the 21-acetate. To a stirred solution of 100 mg. of 9a-fluoro-11B,17a,21-trihydroxy-12p-methyl-l,4-pregnadiene-3,20-dione ZI-acetate 12 in 5 ml. of methanol under nitrogen at 25 C. was added 1.00 ml. of 0.26 M methanolic sodium methoxide. After 15 minutes 0.2 m1. of acetic acid in 1 ml. of water was added and the mixture concentrated nearly to dryness. The residue was taken up in ethyl acetate and the ethyl acetate solution was washed with water dried over magnesium sulfate, and concentrated to dryness. Crystallization of the residue from ethyl acetate gave 911-1111010415, 17a,2l-trihydroxy-IZB-methyl-1,4-pregnadiene-3,20-dione.

EXAMPLE 19 Preparation of 9aChl0r -11B,1 7a,21-Trihydr0xy-12fl- M ethyl-1 ,4-Pregnadien e-3,20-Di0ne 21 -A cetate To a solution of mg. of 9p,11B-epoxy-17u,21-dihydroxy-12fl-methyl 4 pregnene-3,20-dione 21-acetate (prepared as described in Example 9) in 4 ml. of chloroform was added 5 ml. of concentrated hydrochloric acid. The two-phase mixture was stirred at 25 C. for 1 hour. Addition of water and chloroform extraction gave a crude crystalline product which is partly deacetylated. Treatment with 1 m1. of pyridine and 0.5 ml. of acetic anhydride at 25 C. for 18 hours followed by concentration in vacuo and crystallization of the residue from acetoneether afiorded 9a-chloro-11B,1Mil-trihydroxy-12(i-methyl-1,4-pregnadiene-3,20-dione 2l-acetate.

EXAMPLE 20 Preparation of 9u-Chl0r0-1l {3,1 7a,21-Trilzydroxy-125- M ethyl-1 ,4-Pregnadiene-3,20-Dione The 21-alc0hol can be prepared from the 9a-chloro- 11;8,17a,21 trihydroxy 12B methyl 1,4 pregnadiene- 3,20-dione 21-acetate as in Example 13.

EXAMPLE 21 Preparation of 1 704,21 -Dihydr0xy-12fi-Methyl-4-Pregnene- 3,11 ,ZO-TriOne 21 -Acetate Preparation of 1 7u,21-Dihydr0xy-12p-Methyl-4-Pregnene- 3,11,20-Tri0ne l7a,21-dihydroxy-12fl-methyl-4-pregnene-3 ,1 1,20-trione 21-acetate can be converted to the 21-alcohol by the procedure described in Example 11.

EXAMPLE 23 Preparation of 9a-Flu0r0-1 70;,21-Dihydroxy-12p-Methyl- 4-Pregnene-3,I1,20-Trio/1e 21 -Acetate 1.25 grams of chromium trioxide was added in portions to 12.5 ml. of dry pyridine in the cold. To the mixture was added 1.25 g. of 9oc-flUO10-1 1,17a,21-trihydroxy-12flmethyl-4-pregnene-3,20 dione 21-acetate (prepared as described in Example 10) in 2.5 ml. of pyridine. The mixture stood at 20 C. for about 16 hours and was then distributed between other and water. The organic layer was washed with dilute hydrochloric acid, with water, with sodium bicarbonate and finally with saturated salt solution. Removal of the solvent afforded after crystallization the desired 9a-fluoro-17a,21-dihydroxy-12,8-methyl-4-pregnene-3,l 1,20-trione 21-acetate.

13 EXAMPLE 24 Preparation of 1 7 a,21-Dihydrxy-12fl-Me1fhyl-J ,4-Pregnadiene-3,11,20-Trione 21-Acetate 2 grams of chromium trioxide was added in portions of 10 ml. of dry pyridine in the cold. To the mixture was added 1 g. of 11B,17a,21-trihydroxy-12B-methyl-1,4- pregnadiene 3,20-dione 21-acetate (prepared as described in Example 14) in 4 ml. of pyridine. The mixture stood at 20 C. for about 16 hours and was then distributed between ether and water. The organic layer was Washed with dilute hydrochloric acid, with water and sodium bicarbonate and finally with saturated salt solution. Removal of the solvent afforded after crystallization the desired 17a,21-dihydroxy-IZB-methyl-1,4-pregnadiene-3, 1 1 20-trione Z-I-acetate.

EXAMPLE 25 Preparation of 9u-Flu0r0-1 70,21-Dihydr0xy-12[3-Methyl- 1,4-Pregnadiene-3,11,20-Tri0ne 21-Acetate EXAMPLE 26 Preparation of 9a-Chl0r0-17a,21-Dihydr0xy-125-Methyl-1,4-Pregnadiene-3J1,20-Trione 21 -A cetme 2.00 grams of chromium tri-oxide was added in portions to 25 ml. of dry pyridine in the cold. To the mixture was added 1 gram of 9a-chloro-11,8,17a,21trihydroxy- 12/3-methyl-l,4-pregnadiene-3,20-dione ZI-acetate (prepared as described in Example 19) in 2 ml. of pyridine. The mixture stood at 20 C. for 16 hours and was then 14 distributed between ether and Water. The organic layer was washed with dilute hydrochloric acid, with water, with sodium bicarbonate and finally with saturated salt solution. Removal of the solvent altorded after crystallization the desired 9ot-chloro-l7a,21-dihydroxy-12 8- methyl-1,4-pregnadiene-3,11,20-trione ZI-acetate.

EXAMPLE 27 Preparation of 9a-Chl0r0-1 ,21-Dihydr0xy-12 3-Methyl- 1,4-Pregnadiene-3,1 1,20-Tri0ne 'Ihe 9a-chloro-17a,21-dihydroxy-12;8-methyl-l,4-preg nadiene-3,11,20-trione 21-acetate can be converted to the 21-alcohol by the procedure described in Example 13.

Various changes and modifications may be made in the present invention, certain preferred embodiments of which are herein disclosed, without departing from the scope thereof; to the extent that these changes and modifications are within the scope of the appended claims, they are to be considered a part of this invention.

We claim:

1. The process which comprises reacting alkyl 12a-alkyl-3-ethylenedioxy-5, 17 (20 -pregnadien-1 l-one 21-oate with alkali metal hydroxide and then with diazoalkane to form ialkyl 12B-a1kyl-3-ethylenedioxy-5,17(20) pregnadien-l l-one 21-oate.

2. The process which comprises reacting methyl 3-ethylenedioxy-5,17 (20)-pregnadien-11-one 21-oate with potassium hydroxide in the presence of isopropyl alcohol and then with diazomethane to :form methyl 3-ethylenedioxy- 1 Zfi-nrethyl-S, 1 7 20 -pregnadien-1 l-one 21-oate.

References Cited in the file of this patent UNITED STATES PATENTS 2,744,122 'Djerassi et al May 1, 1956 2,752,366 Hogg June 26, 1956 2,759,951 Djerassi Aug. 21, 1956 2,837,464 Nobile June 3, 1958 2,842,568 Herz et a1 July 8, 1958 2,848,464 Fried Aug. 19, 1958 OTHER REFERENCES Fried: I.A.C.S., vol. 76, page 1456 relied on. 

1. THE PROCESS WHICH COMPRISES REACTING ALKYL 12A-ALKYL-3-ETHYLENEDIOXY-5,17(20)-PREGNADIEN-11-ONE 21-OATE WITH ALKALI METAL HYDROXIDE AND THEN WITH DIAZOALKANE TO FORM ALKYL 12B-ALKYL-3-ETHYLENEDIOXY-5,17(20)-PREGNADIEN-11-ONE 21 OATE. 